CN104744505B - A kind of vanadyl class complex and its application - Google Patents
A kind of vanadyl class complex and its application Download PDFInfo
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- CN104744505B CN104744505B CN201510078860.1A CN201510078860A CN104744505B CN 104744505 B CN104744505 B CN 104744505B CN 201510078860 A CN201510078860 A CN 201510078860A CN 104744505 B CN104744505 B CN 104744505B
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- NCXSSEGRSONVQV-UHFFFAOYSA-N CC(C(C1=O)=O)=C1Nc1ccccn1 Chemical compound CC(C(C1=O)=O)=C1Nc1ccccn1 NCXSSEGRSONVQV-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses a kind of vanadyl class complex and its application.The vanadyl class complex, the structure with formula (I) or formula (II)：Wherein L L ' are：L ' is COO or O.The vanadyl class complex is applied to prepare PTEN inhibitor, as drugs for nervous, the action character with efficient, low toxicity, high specificity.
Description
Technical field
The invention belongs to field of medicaments, more particularly, to a kind of vanadyl class complex and its application.
Background technology
PTEN genes (gene of phosphate and tension homology deleted on chromsome
Ten) it is a kind of tumor suppressor gene, it is positioned at chromosome 10q23.3, is made up of 9 extrons, by 403 amino acid code set
Into pten protein matter, with double acid phosphatases activity, i.e., by protein and lipid substrates dephosphorylation.But with major part
Unlike protein tyrosine phosphatase, the albumen preference sloughs the phosphoric acid on phosphoinositide substrate.The albumen negativity regulates and controls
Intracellular phosphatidylinositols -3,4, the level of 5- triphosphoric acids, and the performance suppression cell life of Akt/PKB signalling channels is regulated and controled by negativity
Long effect, therefore, suppresses PTEN and promotes cell growth.
Diperoxovanadate complex is found and is used as the phosphate group hydrolase inhibitor of phosphorylated protein earliest.
The vanadyl class complex being reported has bpv (pic), bpv (HOpic), bpv (phen) and bpv (bipy), they to PTEN and
Protein-tyrosine-phosphatase (PTPs) is respectively provided with inhibitory action.It is thin at present based on inhibitory action of the vanadyl class complex to PTEN
Born of the same parents and zoopery find it to nervous system injury disease (such as：Cerebral ischemia, cerebral hemorrhage, traumatic brain injury and spinal nerve
Member damage), nerve degenerative diseases (such as：Parkinson and Alzheimer disease etc.) and Other diseases there is certain treatment to make
With, but the specificity and validity treated need further checking and improvement.Therefore, new, special, effective, hypotoxicity is researched and developed
Vanadyl complex Central nervous systemic disease treatment it is significant.
The content of the invention
For the disadvantages described above or Improvement requirement of prior art, the invention provides a kind of vanadyl class complex and its should
With its object is to the compound that to PTEN has inhibitory action new by designing aglucon exploitation, for treating nervous system damage
Hinder the diseases such as disease, nerve degenerative diseases, thus solve the big technology of current medicine for central nervous system poor specificity, toxicity
Problem.
To achieve the above object, according to one aspect of the present invention there is provided a kind of vanadyl class complex, with formula (I)
Or the structure of formula (II)：
Or
Wherein L-L ' is：Or
L ' is COO or O.
Preferably, the vanadyl class complex, its L-L ' is：
Preferably, the vanadyl class complex, vanadyl class complex is peroxide (pyridine -2- squaric amides) oxo vanadic acid or double
Peroxide (pyridine -2- squaric amides) oxovanadate.
According to another aspect of the present invention there is provided the application of the vanadyl class complex, it is applied to prepare PTEN
Inhibitor.
Preferably, the vanadyl class complex, it is applied to the medicine for preparing treatment nervous system injury disease.
Preferably, the vanadyl class complex, its be applied to prepare treatment cerebral ischemia, cerebral hemorrhage, traumatic brain injury or
The medicine of spinal neuronal damage.
Preferably, the vanadyl class complex, it is applied to the medicine for preparing treatment nerve degenerative diseases.
Preferably, the vanadyl class complex, it is applied to the medicine for preparing treatment Parkinson or Alzheimer disease.
According to another aspect of the present invention there is provided a kind of PTEN inhibitor medicaments composition, contain the vanadyl class
Complex.
In general, by the contemplated above technical scheme of the present invention compared with prior art, it is used as nervous system medicine
Thing, the action character with efficient, low toxicity, high specificity.Meanwhile, it is prepared simply, and cost is relatively low, is adapted to large-scale production.
Brief description of the drawings
Fig. 1 is vanadyl class complex infrared detection collection of illustrative plates prepared by embodiment 1；
Fig. 2 is vanadyl class complex infrared detection collection of illustrative plates prepared by embodiment 2；
Fig. 3 is vanadyl class complex infrared detection collection of illustrative plates prepared by embodiment 3；
Fig. 4 is vanadyl class complex infrared detection collection of illustrative plates prepared by embodiment 4；
Fig. 5 is the human neuroblastoma cells' experimental result picture of embodiment 5；
Fig. 6 is the glioma cell experimental result picture of embodiment 5；
Fig. 7 is the measuring content of lactic dehydrogenase experimental result picture of embodiment 5, and wherein Fig. 7 a coordinate for vanadyl class is used alone
The treatment effect of thing, Fig. 7 b are the treatment effect that paraquat and vanadyl class complex is used in combination；
Fig. 8 is middle cerebral artery occlusion model in rats experimental result picture.
Embodiment
In order to make the purpose , technical scheme and advantage of the present invention be clearer, it is right below in conjunction with drawings and Examples
The present invention is further elaborated.It should be appreciated that the specific embodiments described herein are merely illustrative of the present invention, and
It is not used in the restriction present invention.As long as in addition, technical characteristic involved in each embodiment of invention described below
Not constituting conflict each other can just be mutually combined.
The vanadyl class complex that the present invention is provided, the structure with formula (I) or formula (II)：
Or
Wherein L-L ' is：OrPreferably
L ' is COO or O.
The vanadyl class complex that the present invention is provided, can by imidazoles -4- formic acid or pyridine -2- squaric amides and vanadic sulfate or
Vanadic anhydride, occurs complex reaction and is made.
It is experimentally confirmed that the vanadyl class complex that the present invention is provided has the effect for suppressing PTEN, press down available for PTEN is prepared
Preparation.PTEN is by its double acid phosphatases activity, by protein and lipid substrates dephosphorylation, negativity regulation and control Akt/PKB letters
Number path suppresses cell growth, therefore, suppresses PTEN and promotes cell growth, thus is damaged in cerebral ischemia, cerebral hemorrhage, traumatic brain
Therapeutic effect is produced on the experimental model of the Other diseases such as wound, spinal neuronal damage, Parkinson's, Alzheimer disease, by
This available PTEN inhibitor further prepares the medicine for the treatment of nervous system injury disease, such as：It is cerebral ischemia, cerebral hemorrhage, traumatic
Brain damage and spinal neuronal damage, nerve degenerative diseases, such as：Parkinson and Alzheimer disease etc..
Compound described herein is most preferably administered in the form of appropriately combined thing., can be with as appropriate composition
It is applicable and all is usually used in administered either systemically or locally composition.Pharmaceutically acceptable carrier should be substantially inert, with
Just do not had an effect with active component.Suitable inert carrier includes water, alcohol, polyethylene glycol, mineral oil or mineral jelly, the third two
Alcohol etc..The pharmaceutical preparations can be formulated into be administered in any suitable mode, in the mankind or veterinary science.
As described below, pharmaceutical composition of the invention can be specifically formulated to solid or liquid form administration, bag
Include those for taking following manner：(1) be administered orally, for example Haust, tablet, bolus, pulvis, granule, applied to tongue
Paste；(2) parenteral, for example subcutaneously, it is intramuscular or intravenous injection, such as sterile solution or suspension；(3) it is local to use
Medicine；(4) in intravaginal or rectum；But in some embodiments, bulk composition simply can be dissolved or suspended in nothing
In bacterium water.In some embodiments, pharmaceutical preparations be it is non-heat, that is, do not raise the body temperature of patient.It is used herein
Wording " effective dose " mean one or more activating agents, material or comprising one or more comprising activating agent of the present invention
Composition is effectively measured for aprowl producing certain required effect.It is generally accepted that being controlled when a kind of activating agent be used to reach
During therapeutic effect, constitute " effective dose " actual dose will be different because of a large amount of conditions, including treated particular condition, disease it is tight
Principal characteristic, the size of patient and health, the approach of administration etc..Medical technician can be easy using method known to field of medicaments
It is determined that appropriate dosage.Wording " pharmaceutically acceptable " is used herein to mean that such compound, material, composition
And/or formulation, they are suitable for contacting with human and animal's tissue in rational medical judgment scope, without excessive poison
Property, stimulation, allergy or other problems or complication, match with rational interests/Hazard ratio.
Wording " pharmaceutically acceptable carrier " used herein represents pharmaceutically acceptable material, component or medium
Thing, such as liquid or solid filler, diluent, excipient, solvent or encapsulating material, participate in delivery or transport main body activating agent
An organ or part to another organ of body or part from body.Each carrier is in the meaning compatible with the other compositions of preparation
Must be " acceptable " in justice.Some examples of materials for potentially acting as pharmaceutically acceptable carrier include：(1) carbohydrate；(2) form sediment
Powder；(3) cellulose and its derivates；(4) powdery twelve month yam glue；(5) malt；(6) gelatin；(7) talcum；(8) excipient；(9) it is oily
Class；(10) glycol；(11) polyalcohol；(12) lipid；(13) agar；(14) buffer；(15) algae；(16) apirogen water；
(17) isotonic saline solution；(18) Green's formula solution；(19) ethanol；(20) phosphate buffer solution；(21) it is other to be used in pharmaceutical preparation
In non-toxic compatible material.In some embodiments, one or more activating agents can contain basic functionality, such as amino
Or alkyl amino, it is thus possible to generate pharmaceutically acceptable salt with pharmaceutically acceptable acid.Term " can pharmaceutically connect
The salt received " represents relative nontoxic, the compounds of this invention inorganic and organic acid addition salt in this respect.These salt can be most
Prepared on the spot during whole the compounds of this invention isolation and purification, or individually make the free of purified the compounds of this invention
Alkali form and suitable organic or inorganic acid reaction, then separate generated salt.Representative alkali metal or alkali salt include
Lithium, sodium, potassium, calcium, magnesium, aluminium salt etc..The example of pharmaceutically acceptable antioxidant includes (1) water soluble antioxidant；(2) it is oily
Soluble antioxidant；(3) metal-chelator；Preparation is prepared as follows：By activating agent of the present invention and liquid-carrier or finely pulverized
Solid carrier or the two uniform close association, then shape if necessary product.
When humans and animals are administered as medicine for the compounds of this invention, they can be as former state or to be used as drug regimen
Thing is administered, combination of the composition for example containing 0.1-99.5% active components with pharmaceutically acceptable carrier.Except
Combinations thereof beyond the region of objective existence, it is possible to use the covering wherein containing appropriate therapeutic agent, such as plaster, bandage, dressing, pad of cotion.
As mentioned previously, therapeutic combination can again support, device, be administered on Prostheses and implants.
It is embodiment below：
Embodiment 1
A kind of vanadyl class complex, its chemical name is peroxide (imidazoles -4- formic acid) oxo vanadic acid, is abbreviated as pV (imc),
Structure is as follows：
Synthetic method is as follows：
Concrete operations are：Under argon gas protection, VOSO is taken4 .3H2O (1.00g, 4.6mmol) is dissolved in the distilled water of 5mL degassings
In, the 5mL aqueous solution dissolved with imidazoles -4- formic acid (1.03g, 9.2mmol) is added, by the NaOH for being slowly added into 11mL 2M
(0.90g, 23.0mmol) solution adjusts pH value to 12, adds and be stirred overnight after NaOH solution, produces a large amount of precipitations, quick mistake
Filter, with cold water and washed with ether filter cake, is drying to obtain target compound peroxide (imidazoles -4- formic acid) oxo vanadic acid (pV (imc)),
Yield is 78%.Product structure is determined by infrared, mass spectrum.IR v(KBr):3439,1635 (CN), 960 (VO) cm-1, it is infrared
Collection of illustrative plates is as shown in Figure 1.
Embodiment 2
A kind of vanadyl class complex, its chemical name is double peroxide (imidazoles -4- formic acid) oxovanadates, is abbreviated as bpV
(imc), structure is as follows：
Synthetic method is as follows：
Concrete operations are：Take V2O5(1.43g, 7.84mmol), KOH (1.04g, 18.53mmol) is added to 15mL degassings
Stirred 5 minutes in distilled water, solution can gradually become green, 2mL 30% H is added into the solution of greening2O2, stir 25 points
Clock, after solid gradually dissolves, adds 12mL30% H2O2, stir 15 minutes, now add dissolved with imidazoles -4- formic acid
The 20mL water of (1.76g, 15.68mmol) and the mixed solution of 5mL ethanol, react 30 minutes at room temperature, produce solid, filter,
Double peroxide (imidazoles -4- formic acid) oxovanadates (bpV (imc)) of target product are drying to obtain, yield is 84%.Product structure leads to
Infrared, mass spectrum is crossed to determine.IR v(KBr):(OO) cm of 3456,1621 (CO), 947 (VO), 842-1, the infared spectrum such as institute of accompanying drawing 2
Show.
Embodiment 3
A kind of vanadyl class complex, its chemical name is peroxide (pyridine -2- squaric amides) oxo vanadic acid, is abbreviated as pV
(pis), structure is as follows：
Synthetic method is as follows：
Concrete operations are：Under argon gas protection, VOSO is taken4 .3H2O (1.00g, 4.6mmol) is dissolved in the distilled water of 5mL degassings
In, the 5mL aqueous solution dissolved with pyridine -2- squaric amides (1.75g, 9.2mmol) is added, by being slowly added into 11mL 2M's
NaOH (0.90g, 23.0mmol) solution adjusts pH value to 12, adds and be stirred overnight after NaOH solution, produces a large amount of precipitations, quickly
Filtering, with cold water and washed with ether filter cake, is drying to obtain target compound peroxide (pyridine -2- squaric amides) oxo vanadic acid (pV
(pis)), yield is 68%.Product structure is determined by infrared, mass spectrum.IR v(KBr):3452,1683 (CO), 1013 (VO)
cm-1, infared spectrum is as shown in Figure 3.
Embodiment 4
A kind of vanadyl class complex, its chemical name is double peroxide (pyridine -2- squaric amides) oxovanadates, is abbreviated as
BpV (pis), structure is as follows：
Synthetic method is as follows：
Concrete operations are：Take V2O5(1.43g, 7.84mmol), KOH (1.04g, 18.53mmol) is added to 15mL degassings
Stirred 5 minutes in distilled water, solution can gradually become green, 2mL 30% H is added into the solution of greening2O2, stir 25 points
Clock, after solid gradually dissolves, adds 12mL30% H2O2, stir 15 minutes, now add dissolved with pyridine -2- sides acyl
The 20mL water of amine (2.98g, 15.68mmol) and the mixed solution of 5mL ethanol, react 30 minutes at room temperature, produce solid, mistake
Filter, is drying to obtain double peroxide (pyridine -2- squaric amides) oxovanadates (bpV (pis)) of target product, yield is 76%.Product
Structure is determined by infrared, mass spectrum.IR v(KBr):(OO) cm of 3194,1617 (CO), 960 (VO), 816-1, infared spectrum is as schemed
Shown in 4.
Embodiment 5
Be below in embodiment 1 to 4 the vanadyl class complex that synthesizes in SH-SY5Y, U251 cell line and SD rats
Effect.
(1) human neuroblastoma cells test
Containing PTEN, brain is originated, human neuroblastoma cells strain SH-SY5Y handles 1 through ECS (extracellular fluid)
After hour, then handled 1 hour respectively with the vanadyl class complex (200nM) synthesized in embodiment 1 to 4, then use western
Blot technology for detection Akt activity.Akt is a kind of Protein Serine/threonine kinase, and P-Akt is the performance shape of Akt protein activations
Formula, can promote cell growth after Akt activation, suppress Apoptosis.As shown in Figure 5：The processing of four kinds of vanadyl complexs (200nM)
P-Akt in cell is caused to express apparently higher than control group CON (n=6, ANOVA test, * P respectively<0.05vs.CON；t-Akt
For Akt total protein contents), point out that there is protective effect.
(2) glioma cell is tested
By the glioma cell line U251 of PTEN gene delections through ECS handle 1 hour after, then with embodiment 1 to 4 synthesis
Vanadyl class complex (200nM) handle 1 hour respectively, then with western blot technology for detection Akt activity.Such as Fig. 6 institutes
Show：Vanadyl complex (200nM) processing does not cause the expression of p-Akt in cell to change (n=6, ANOVA test；T-Akt is
Akt total protein contents).Because known PTEN can suppress p-Akt activity, this test result indicate that, the enhancing of this kind of vanadyl complex
The effect of Akt activity is the mediation by PTEN.
(3) LDH (lactic dehydrogenase) assay is tested
LDH (lactic dehydrogenase) is very important a kind of glycolytic ferment in living cells, when cell sustains damage or cell
When film is damaged, LDH can be discharged, so LDH burst size can embody cell survival conditions or degree of injury.Such as Fig. 7 a institutes
Show, after SH-SY5Y cells are handled respectively with the vanadyl class complex synthesized in embodiment 1 to 4 (200nM, 2 μM) 12 hours,
The processing of this kind of vanadyl complex does not increase LDH burst sizes not only but also fewer than ECS treatment groups (n=6, ANOVA test), table
Such bright complex does not have cytotoxic effect in 200nM-2 μM of concentration range.In addition, when cell is damaged through PQ (paraquat)
Processing, the group substantially increases (Fig. 7 b n=6, ANOVA test than the LDH burst sizes of PQ+ vanadyl complex groups；*P<
0.05vs.control；#P<0.05vs.PQ), show that such complex has cytoprotection.
(4) rat MCAO (middle cerebral artery occlusion) model experiment
MCAO operations are carried out to SD rats, ischemic revascularization after 1.5 hours is triggered ischemical reperfusion injury, built with this
Vertical cerebral apoplexy model.After blood vessel Reperfu- sion 3 hours, inject the vanadyl class synthesized in embodiment 1 to 4 respectively through lateral ventricle of rat brain and match somebody with somebody
Compound (2 μM).Perfusion takes brain after 24 hours, carries out TTC dyeing.TTC (2,3,5-triphenyltetrazolium chloride) is fat-soluble light
Sensitive compound, it dyes the ischemic infarct size that can be used to detect mammalian tissues.Experimental result is as shown in Figure 8：Injection
The cerebral ischemia area of vanadyl class complex animal is substantially than ischemic areas small (n=9, the ANOVA of injecting normal saline control group
test；*P<0.05vs.CON).Show that such Novel oxygen vanadium complex has protective effect to cerebral apoplexy ischemic injuries.
As it will be easily appreciated by one skilled in the art that the foregoing is only presently preferred embodiments of the present invention, it is not used to
The limitation present invention, any modification, equivalent and the improvement made within the spirit and principles of the invention etc., it all should include
Within protection scope of the present invention.
Claims (8)
1. a kind of vanadyl class complex, it is characterised in that the structure with formula (I) or formula (II)：
Wherein, when the vanadyl class complex has the structure of formula (I), L-L ' is：The vanadyl class is matched somebody with somebody
When compound has the structure of formula (II), L-L' is：
When L-L' isWhen, L' is COO, and the N atoms that wherein L is upper 3rd are coordinated with V, and O atom is coordinated with V in L'；
When L-L' isWhen, L' is O, and the wherein outer N atoms of L ring are coordinated with V.
2. vanadyl class complex as claimed in claim 1, it is characterised in that the L-L ' is：
3. a kind of application of vanadyl class complex as claimed in claim 1 or 2, it is characterised in that applied to preparation people the 10th
The inhibitor of the phosphatase of number chromosome deficiency and the expressing protein of tensin homologous gene.
4. the application of vanadyl class complex as claimed in claim 3, it is characterised in that damaged applied to treatment nervous system is prepared
Hinder the medicine of disease.
5. the application of vanadyl class complex as claimed in claim 4, it is characterised in that treat cerebral ischemia, brain applied to preparing
The medicine of bleeding, traumatic brain injury or spinal neuronal damage.
6. the application of vanadyl class complex as claimed in claim 3, it is characterised in that treat nervus retrogression applied to preparing
The medicine of disease.
7. the application of vanadyl class complex as claimed in claim 6, it is characterised in that applied to prepare treatment Parkinson or Ah
The medicine of Alzheimer's disease.
8. the inhibitor medicaments of a kind of phosphatase of No. 10 chromosome deficiency of people and the expressing protein of tensin homologous gene
Composition, it is characterised in that contain vanadyl class complex as claimed in claim 1 or 2.
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| JP3270695B2 (en) * | 1996-12-02 | 2002-04-02 | 山本化成株式会社 | Method for producing vanadyl naphthalocyanine compound |
| EP1755574A4 (en) * | 2004-04-06 | 2009-05-13 | Semafore Pharmaceuticals Inc | Pten inhibitors |
| WO2009091332A1 (en) * | 2008-01-17 | 2009-07-23 | Kui Liu | Methods for in vitro maturation of ovarian follicles |
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